Pharmaceutical compositions containing substituted 2-oxo-indolines and the use thereof to treat anxiety and tension

ABSTRACT

A pharmaceutical composition containing as an active ingredient a 2-oxo-indoline substituted on the benzene ring by C1-C3 alkyl, C1-C3 alkoxy, halo, or trifluoromethyl, and a method of using the substituted 2-oxoindoline in relieving a condition associated with anxiety, tension, or a like emotional disturbance.

United States Patent Molloy May 6, 1975 [54] PHARMACEUTICAL COMPOSITIONS3,691,199 9/1972 Kobaysahi et al .t 260/325 R CONT SUBSTITUTED 3,720,7713/1973 Canas-Rodriguez et al 424/274 3,723,457 3/1973 Hirose et al424/274 Z-OXO-INDOLINES AND THE USE THEREOF TO TREAT ANXIETY AND TENSIONInventor: Bryan B. Molloy, Indianapolis, Ind.

Eli Lilly and Company, Indianapolis, Ind.

Filed: Dec. 26, 1973 Appl. No.: 427,947

Assignee:

References Cited UNITED STATES PATENTS l/l972 McManus et al. 260/325 RPrimary ExaminerStanley J. Friedman Attorney, Agent, or FirmWilliam C.Martens, Jr; Everet F. Smith [57} ABSTRACT A pharmaceutical compositioncontaining as an active ingredient a 2-oxoindoline substituted on thebenzene ring by (l -C alkyl, C,-C alkoxy, halo, or trifluoromethyl, anda method of using the substituted 2 oxoindoline in relieving a conditionassociated with anxiety, tension, or a like emotional disturbance.

16 Claims, No Drawings PHARMACEUTICAL COMPOSITIONS CONTAININGSUBSTITUTED Z-OXO-INDOLINES AND THE USE THEREOF TO TREAT ANXIETY ANDTENSION BACKGROUND AND SUMMARY OF THE INVENTION This invention relatesto therapeutic compositions, and to a process for achieving therapeuticaction.

It has been discovered that certain substituted 2-oxoindolines have auseful effect on the central nervous system. In particular, it has beendiscovered that these compounds exhibit a sedative-hypnotic effect andcan be used in the treatment of conditions associated with anxiety,tension, or other emotional disturbance.

2-Oxo-indolines are widely recognized in the art; see, for example,British Pat. No. l,247,ll3 and Belgian Pat. No. 756,447. Nowhere,however, does the art recognize that ring-substituted 2-oxo-indolineshaving the structure defined herein exhibit a useful therapeuticactivity. This discovery forms the basis of this invention.

Specifically, this invention relates to a pharmaceutical composition forrelieving a condition associated with anxiety, tension, or likeemotional disturbance comprising a therapeutically effective dose of anoxoindoline of the formula in which R is C -C alkyl, C C; alkoxy, halo,or trifluoromethyl, in association with a pharmaceutical carrier.

Another embodiment of this invention relates to a method of treating apatient to relieve a condition associated with anxiety, tension, or likeemotional disturbance which comprises administering to said patient anoxo-indoline of the foregoing formula.

DETAILED DESCRIPTION OF THE INVENTION The active compounds of thecomposition of this invention and useful in the process of thisinvention have the formula 2-Oxo-4-iodoindoline;

2 -Oxo-6-bromoindoline;

2-Oxo-5-fluoroindoline;

2-Oxo-6-iodoindoline;

2-Oxo-4-trifluoromethylindoline;

2-Oxo-5-trifluoromethylindoline; and the like.

Oxo-indolines such as the above can be prepared by any of severalrecognized methods.

One standard chemical procedure which is available is that commonlyreferred to as the Stolle synthesis. This is developed at some depth inP. L. Julian et al., Heterocyclic Compounds, Vol. 3, John Wiley andSons, Inc., New York (I952), pp. l42-l46, and involves ring-closure ofan a-haloacetanilide to the corresponding oxo-indoline. In applying thismethod to the preparation of compounds defined herein, the particulara-haloacetanilide which is employed will be ringsubstituted so as toreflect the position and identity of the ring substituent of the finalproduct.

Another method which is available comprises reduction of thecorresponding isatin to the oxo-indoline. This procedure also isdescribed in the aforementioned publication by P. 1... Julian et al., atpp. I29-l30, thereof.

The isatins which are reduced to the corresponding oxo-indolines can beprepared from readily available starting materials in accordance withthe following sequence:

NaeSOa. HONHB.HCI

NH: Cl aC-CH (OH) 2 R 0 ll NH-CCH=NOH Polyphosphorl c act d NaOH O l HThe foregoing sequence is merely representative of the preparation ofisatins. Isatins are well known in the art and are available fromvarious routes, see, for example, D. J. Bauer and P. W. Sadler, Brit. J.Pharmacol., 15, (1960) pp. 101-110.

In the foregoing sequence, the source of the isatin is a substitutedaniline. Typically, the substituted aniline, in the form of its acidaddition salt, is converted to the corresponding isonitrosoacetanilideby reaction with chloral hydrate in the presence of sodium sulfatefollowed by treatment of the resulting reaction mixture withhydroxylamine hydrochloride. The reaction typically is carried out inwater with the reaction mixture being gently heated for a short periodof time.

The next step in the synthesis involves the conversion of theisonitrosoacetanilide to its corresponding isatin. This ring-closurereaction can be accomplished by treating the isonitrosoacetanilide withpolyphosphoric acid at a moderately elevated temperature. Sinceringclosure occurs in the position ortho to the anilide nitrogen, twostructures can be formed, depending upon the position of the substituenton the ring of the isonitrosoacetanilide and the direction of theringclosure. 1n the event two products are formed, separation typicallycan be accomplished by a successive precipitation technique. Thereaction product mixture is first brought into aqueous solution byaddition of alkali. Precipitation of the two products typically is pHdependent, and one product is precipitated from the solution byacidifying the mixture to a moderately acidic pH of from about 3 toabout 5. This product is then collected by filtration or extraction, andthe collected product is further purified by standard techniques such asrecrystallization. The filtrate then is further acidified, for example,to about pH 1 to effect isolation of the other product. This product isthen separately collected and purified by recrystallization from anappropriate solvent.

The final step in the synthesis from isatins of the oxoindolines used inthis invention involves the conversion of the isatin to itscorresponding ring-substituted 2-oxoindoline. This can be accomplishedby treating the isatin with anhydrous hydrazine at reflux in anappropriate moderately low boiling solvent such as a lower alkylalcohol. The resulting unisolated isatin derivative, in the form of ahydrazone, is then reacted reductively with a sodium alkoxide. Theoverall effect is the replacement of the keto function in the 3-positionwith a methylene group, thereby achieving formation of the oxo-indoline.Recovery can be accomplished by evaporating the solvent, dissolving theresidue in water to achieve solution of the water-soluble by-products,and acidification of the mixture to produce precipitation of the finalproduct. The final product can then be purified by recrystallizationfrom a suitable solvent.

In accordance with this invention, the pharmaceutically activeoxo-indolines can be administered alone or, preferably, in associationwith a pharmaceutical carrier. The pharmaceutical carrier is selected onthe basis of the chosen route of administration and in accordance withstandard pharmaceutical practice. For example, the oxo-indolines can beadministered orally, either alone, in capsule form, or in the form oftablets or capsules containing excipients such as starch, milk sugar,certain types of clay, and the like. The oxoindolines can also beadministered orally in the form of elixirs or oral suspensions which cancontain coloring and/or flavoring agents. The oxo-indolines can also beadministered parenterally, and, for use in this route of administration,they can be prepared in the form of sterile solutions containing othersolutes such as salt or glucose in sufficient quantity to make thesolution isotonic. For intramuscular administration, the oxoindolinecompositions can be prepared in an oil base such as a peanut or sesameoil.

The oxo-indolines of this invention are administered in pharmaceuticallyeffective amounts. Generally, these will range from about 0.5 to about500 milligrams per day, and preferably from about 2 to about 200milligrams per day. However, in general, the dosage will depend uponparticular circumstances, and these may differ from case to case. Forexample, the dosage levels will vary with the age, weight, and generalhealth of the recipient as well as various other factors which may bepeculiar to the particular recipient. in general, if the oxo-indoline isadministered by a parenteral route, a lower dosage, for example, fromabout 0.1 milligram to about 250 milligrams of the oxo-indoline can beemployed. Preferably the oxo-indoline composition is in unit dosageform. This expression as used herein refers to a physically discreteunit containing a predetermined dose of the oxo-indoline either alone orin association with a pharmaceutically acceptable carrier or excipient.The unit dosage form may contain from about 0.5 to about 500 milligramsof the active oxo-indoline ingredient.

The following examples are provided to further illustrate the teachingof this invention and are by no means intended to be limiting upon thescope thereof.

EXAMPLE To a suspension of 15 g. of 6-chloroisatin in 180 ml. of ethanolwere added 30 ml. of hydrazine (97%), and the resulting solution wasrefluxed for 6 hours. A sodium ethoxide solution was prepared bydissolving 8.3 g. of sodium in 350 ml. of ethanol. The reaction mixturefrom the reaction of b-chloroisatin and hydrazine, while hot, was slowlyadded to the sodium ethoxide solution maintained at 70C. Upon completionof the addition, the resulting mixture was refluxed for about 16 hours.The solvent was then removed in vacuo, and the residue was added toabout 800 g. of ice water. The pH of the resulting mixture was adjustedto about pH 1-2 by addition of concentrated hydrochloric acid, and thesolids which formed were removed by filtration and washed with water.Recrystallization from a mixture of ethanol and water afforded 7.5 g. of2-oxo-6- chloroindoline, m.p. 189-192C.

Analysis, calculated for C H CINO C, 57.33; H, 3.61; N, 8.36; O, 9.55;C1, 21.15.

Found: C, 57.37; H, 3.80; N, 8.31;O, 9.29; C1, 20.85.

Using procedures similar to the above, the following compounds areprepared. 2-Oxo-6-methylindoline; m.p. 17 l173C.

Anal. Calcd for C H NO:

C, 73.45; H, 6.16; N, 9.52; O, 10.87.

Found: C, 73.18; H, 6.12; N, 9.80; O, 10.97. 2-Oxo-6-methoxyindoline;m.p. 152-155C.

Anal. Calcd for C H NO C, 66.24; H, 5.56; N, 8.58; O, 19.61.

Found: C, 65.97; H, 5.39; N, 8.85; O, 19.75. 2-Oxo-4-methylindoline;m.p. 204206C.

Anal. Calcd for C H NO:

C, 73.45; H, 6.16; N, 9.52; O, 10.87.

Found: C, 73.29; H, 6.36; N, 9.58; O, 10.80. 2-Oxo-5-chloroindoline;m.p. 197-199C. 2-Oxo-4-chloroindoline; m.p. 21 1-213C.

Anal. Calcd for C H CINO:

C, 57.33; H, 3.61; N, 8.38; O, 9.55; C1, 21.15.

Found: C, 57.54; H, 3.88; N, 8.32; O, 9.69; C1, 21.21.2-Oxo-6-f1uoroindoline; m.p. l39-141C.

Anal. Calcd for C H FNO:

C, 65.58; H, 4.00; N, 9.23.

Found: C, 65.76; H, 4.12; N, 9.35. 2-Oxo-7-chlorindoline;2-Oxo-5-methoxyindoline', m.p. 151C.

Anal. Calcd for C H NO C, 66.25; H, 5.56; N, 8.58; O, 19.61.

Found: C, 66.12; H, 5.52; N, 8.30; O, 19.83.

' 2-Oxo6-trifluoromethylindoline; m.p. 176-179C.

Anal. Calcd for C H F NO: C, 53.74; H, 3.00, N, 6.96

milligrams of test compound per milliliter. The individ ual weights ofthree canaries are determined, and a pre determined amount of the acaciasuspension, measured in milligrams of test compound per kilogram of bodyweight of the canary, is orally injected. The birds are placed in alighted area and observed for a period of one hour, and the length oftime that each bird sleeps is noted.

In the Table following is provided the tranquilizing activity of theoxo-indolines which are used in the method and are present in thecomposition of this in' vention. This activity is determined by means ofthe aforedescribed test procedure.

TABLE ACTIVITY OF 2-OXO-INDOLINES Milligrams per kilogram weight ofcanary 160 so 20 1o 5 2.5

R No. Min. No. Min. No. Min. No. Min. No. Min. No. Min No. Min.

P 6-Methy1 2 23 3 1a 2 3o 1 10 1 2 P 1 3 j G-Methoxy 1 3 3 1s 0 -j y i 32a 1 a 6-Ch1oro 3 37 3 3s 0 j 4-Ch1oro 3 1 l2 0 i l 6-Fluoro i 3 42 1 73 13 o l 1 iSflethoxy a 11 1 11 1 1o 5 o v-neuh l 3 6 33 2 17 2 a 0 a y1 i 7 2 5 o l l jS-Fluoro 3 l 28 3 l as 3 20 o 1 2 1 s l 5-Chloro 2 13 Qi i 17-Chloro 3 1 37 o l i IG-Trifluoromethyl 3 4s 1 22 1 12 l 5ll-Trifluoromethy]. 3 l 22 3 i 18 2 2O 4 l t l 1 Footnotes-- test groupin which sleep was induced.

"No." refers to the number of canaries of the Unless otherwiseindicated, a test group comprises three canar ies "Min." refers to thecombined total minutes of sleep which were recorded divided by thenumber of Canaries in the group.

Test group is composed of six canaries.

I claim:

1. A pharmaceutical composition for relieving a condition associatedwith anxiety and tension comprising a therapeutically effective dose ofan oxoindoline of the formula 7. Composition of claim 1, in which R istrifluoro methyl.

8. A method of treating a patient to relieve anxiety and tension, whichcomprises administering to said patient a pharmaceutically effectiveamount of an exeindoline of the formula in which R is C,C alkyl, C -Calkoxy, halo, or trifluoromethyl.

9. Method of claim 8, in which the indoline is administered at the rateof about 0.5 to about 500 milligrams per day,

10. Method of claim 9, in which the indoline is ad ministered at a rateof about 2 to about 200 milligrams per day.

11. Method of claim 8, in which the indoline is administered orally,

12. Method of claim 8, in which R is methyl.

13. Method of claim 8, in which R is methoxyx 14. Method of claim 8, inwhich R is halo.

15. Method of claim 14, in which R is chloro or fluoro.

16. Method of claim 8, in which R is trifluoromethyl

1. A pharmaceutical composition for relieving a condition associatedwith anxiety and tension comprising a therapeutically effective dose ofan oxo-indoline of the formula
 2. Composition of claim 1 which comprisesfrom about 0.5 to about 500 milligrams of the indoline in associationwith a pharmaceutical carrier.
 3. Composition of claim 1, in which R ismethyl.
 4. Composition of claim 1, in which R is methoxy.
 5. Compositionof claim 1, in which R is halo.
 6. Composition of claim 5, in which R ischloro or flUoro.
 7. Composition of claim 1, in which R istrifluoromethyl.
 8. A METHOD OF TREATING A PATIENT TO RELIEVE ANXIETYAND TENSION, WHICH COMPRISES ADMINISTERING TO SAID PATIENT APHARMACEUTICALLY EFFECTIVE AMOUNT OF AN OXO-INDOLINE OF THE FORMULA 9.Method of claim 8, in which the indoline is administered at the rate ofabout 0.5 to about 500 milligrams per day.
 10. Method of claim 9, inwhich the indoline is administered at a rate of about 2 to about 200milligrams per day.
 11. Method of claim 8, in which the indoline isadministered orally.
 12. Method of claim 8, in which R is methyl. 13.Method of claim 8, in which R is methoxy.
 14. Method of claim 8, inwhich R is halo.
 15. Method of claim 14, in which R is chloro or fluoro.16. Method of claim 8, in which R is trifluoromethyl.